The unambiguous demonstration of opioid receptor types, and their endogenous ligands, the endorphins, together with a diverse range of synthetic ligands, has created exciting opportunities for research highly relevant to drug abuse. One major objective of this project is to continue the process of defining new opioid receptor subtypes. This process is optimally accomplished by synergistic collaborations with medicinal chemists to develop (a) selective high affinity ligands for each subtype (b) irreversible ligands with receptor subtype specificity and (c) enantiomeric pairs of these ligands for detection of receptor mediated effects. Delta receptor antagonists attenuate alcohol consumption, block morphine tolerance and dependence and decrease cocaine-reinforcement. . Recent work, using antisense DNA, has further delineated four subtypes of the delta receptor. The determination of delta receptor subtypes may lead to new medicines for the treatment of alcoholism and drug addiction. The strong association of high risk behaviors related to the spread of HIV with opioid addiction makes the effort to develop new treatment medications for opioid addiction highly related to the fight against AIDS. Collaborative efforts with Dr. Rice's lab have led to the identification and biological evaluation of highly selective nonpeptide delta agonists. Converging lines of investigation suggest that kappa receptor antagonists may be useful for the treatment of depression, anxiety, psychosis and craving. In this fiscal year our collaborative project with Dr. F. Ivy Carroll has identified novel and selective mu and kappa receptor antagonists. Studies reported last year demonstrated up to four subtypes of kappa opioid receptors in rat, guinea pig and human brain, suggesting that it may be possible to develop kappa agonists devoid of psychotomimetic side effects. More recent studies using the novel radioligand [125I]IOXY have resolved additional kappa receptor subtypes.Other studies have shown that enantiomers of the potent methylfentanyl analog, RTI-4614-4, likely bind to different domains of the mu receptor, indicating that manipulation of stereochemistry can be used to produce domain-specific ligands. The notion that dysfunction of the CNS opioid receptor/endorphin system underlies certain mental illnesses, and contributes to drug abuse, remains a viable, but unproved, hypotheses.